Parasitic protozoal infections are responsible for a wide variety of diseases of medical and veterinary importance, including malaria in man and various coccidioses in birds, fish and mammals. Many of the diseases are life-threatening to the host and cause considerable economic loss in animal husbandry, such as species of Eimeria, Theileria, Babesia, Cryptosporidium, Toxoplasma (such as Toxoplasma brucei, African sleeping sickness and Toxoplasma cruzi, Chagas disease) and Plasmodium (such as Plasmodium falciparum), and the Mastigophora such as species of Leishmania (such as Leishmania donovani). Another parasitic organism of increasing concern is Pneumocytis carinii, which can cause an often fatal pneumonia in immunodeficient or immunocompromised hosts, including those infected with HIV.
Malaria is one of the major disease problems of the developing world. The most virulent malaria-causing parasite in humans is the parasite Plasmodium falciparum, which is the cause of hundreds of millions of cases of malaria per annum, and is thought to cause over 1 million deaths each year, Breman, J. G., et al., (2001) Am. Trop. Med. Hyg. 64, 1-11. One problem encountered in the treatment of malaria is the build-up of resistance by the parasite to available drugs. Thus, there is a need to develop new antimalarial drugs.
A group of 3,5-dihalo-2,6-dialkyl-4-pyridinol derivatives (the tautomeric form of 4-pyridones) is described in U.S. Pat. No. 3,206,358 as having anticoccidial activity.
European Patent Application No. 123239 discloses combinations of the aforementioned 4-pyridinol derivatives with antiprotozoal naphthoquinones, e.g. antimalarial naphthoquinones, in a potentiating ratio.
PCT Patent Application No. WO 91/13873 A1 discloses a class of 4-pyridone derivatives which exhibit activity against protozoa, in particular against the malarial parasite Plasmodium falciparum, and species of Eimeria as well as the parasitic organism Pneumocytis carinii. It has been found that compounds according to the present invention, generically disclosed in WO 91/13873 A1, and having a specific substitution pattern, exhibit improved properties over those compounds specifically disclosed in WO 91/13873 A1.